Pain: A Review of Interleukin-6 and Its Roles in the Pain of Rheumatoid Arthritis.

Pain is a major and common symptom reported as a top priority in patients with rheumatoid arthritis (RA). Intuitively, RA-related pain is often considered to be a natural consequence of peripheral inflammation, so treatment of RA is expected to manage pain concurrently as part of inflammation control. However, pain in patients with RA can be poorly correlated with objective measures of inflammation, for example, in patients who are otherwise in remission. Joint damage appears to account for only a fraction of this residual pain. Emerging evidence suggests that alteration of peripheral and central pain processing contributes to RA-related pain; this is parallel to, but somewhat independent of, joint inflammation. Interleukin (IL)-6 is a proinflammatory cytokine that contributes to the pathogenesis of RA. It exerts systemic effects via signaling through soluble forms of the IL-6 receptor ("trans-signaling"). Evidence from preclinical studies demonstrates that intra-articular IL-6 can produce long-lasting peripheral sensitization to mechanical stimulation and suggests an important role for IL-6 in central pain sensitization. This may be partly explained by its ability to activate neurons through trans-signaling, affecting nociceptive plasticity and nerve fiber regrowth. Local activity at neuron endings may culminate in altered pain processing in the central nervous system because of persistent signaling from sensitized peripheral neurons. Peripheral and central sensitization can promote the development of chronic pain, which can have a significant impact on patients' health and quality of life. A proportion of pain in RA may be more appropriately managed as an entity separate from inflammation. Both the peripheral and central nervous systems should be recognized as important potential systems targeted by RA. The substantial burden of RA-related chronic pain suggests that pain should be a key focus in RA management and should be assessed and addressed early and separately from the inflammatory component.